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    Clinical Trial Results:
    A randomised, sequential, cross-over trial assessing pharmacokinetic and pharmacodynamic responses after micro-doses of ZP4207 administered subcutaneously to patients with type 1 diabetes mellitus under euglycaemic and hypoglycaemic conditions and with reference to freshly reconstituted lyophilized glucagon

    Summary
    EudraCT number
    		 2016-002617-21
    Trial protocol
    		 DE  
    Global end of trial date
    05 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2020
    First version publication date
    29 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZP4207-16098
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02916251
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zealand Pharma
    Sponsor organisation address
    Sydmarken 11, Søborg, Denmark, 2860
    Public contact
    Dorte Skydsgaard, Zealand Pharma A/S, +45 5060 3767, DSkydsgaard@zealandpharma.com
    Scientific contact
    Ramin Tehranchi, Zealand Pharma A/S, +45 5060 3793, RTehranchi@zealandpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the PK and PD properties of ZP4207 4 mg/mL following s.c. administration at euglycemic and hypoglycemic conditions in adult patients with T1DM.
    Protection of trial subjects
    The trial was conducted in accordance of the World Medical Association Declaration of Helsinki, current guidelines for GCP and local regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    23
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients were recruited from a single site in Germany.

    Pre-assignment
    Screening details
    		 40 patients were screened and 23 patients were eligible and randomised.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject
    Blinding implementation details
    For the 3 lowest dose levels (0.03 mg, 0.08 mg and 0.2 mg), the patients received 1 ZP4207 dose and 1 Glucagon™ dose at euglycemic conditions on Day 1, while 1 ZP4207 dose was administered at hypoglycemic conditions on Day 2 (Visits 2-4). Patients were randomised to one of 6 treatment sequences (different order of the three lowest dose levels as well as the order of ZP4207 and Glucagon on day 1). All patients received 2 administrations of ZP4207 0.6 mg (euglycemic then hypoglycemic) at Visit 5.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 0.03 mg ZP4207 - euglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.03 mg ZP4207 at euglycemic state however at different trial visits.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZP4207 - 0.03 mg
    Investigational medicinal product code
    Other name
    Dasiglucagon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.03 mg ZP4207 in solution was administered via disposable dosing syringe. The subcutaneous injections was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Arm title
    		 0.08 mg ZP4207 - euglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.08 mg ZP4207 at euglycemic state however at different trial visits.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZP4207 - 0.08 mg
    Investigational medicinal product code
    Other name
    Dasiglucagon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.08 mg of ZP4207 was administered via disposable dosing syringe. The subcutaneous injection was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Arm title
    		 0.2 mg ZP4207 - euglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.2 mg ZP4207 at euglycemic state however at different trial visits
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZP4207 - 0.2 mg
    Investigational medicinal product code
    Other name
    Dasiglucagon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.2 mg ZP4207 in solution was administered via disposable dosing syringe. The subcutaneous injection was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Arm title
    		 0.6 mg ZP4207 - euglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.6 mg ZP4207 at euglycemic state, however at different trial visits
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZP4207 - 0.6 mg
    Investigational medicinal product code
    Other name
    Dasiglucagon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.6 mg ZP4207 in solution was administered via disposable dosing syringe. The subcutaneous injection was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Arm title
    		 0.03 mg ZP4207 - hypoglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.03 mg ZP4207 at hypoglycemic state, however at different trial visits
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZP4207 - 0.03 mg
    Investigational medicinal product code
    Other name
    Dasiglucagon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.03 mg ZP4207 in solution was administered via disposable dosing syringe. The subcutaneous injection was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Arm title
    		 0.08 mg ZP4207 - hypoglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.08 mg ZP4207 at hypoglycemic state, however at different trial visits
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZP4207 - 0.08 mg
    Investigational medicinal product code
    Other name
    Dasiglucagon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.08 mg of ZP4207 was administered via disposable dosing syringe. The subcutaneous injection was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Arm title
    		 0.2 mg ZP4207 - hypoglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.2 mg ZP4207 at hyopglycemic state, however at different trial visits
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZP4207 - 0.2 mg
    Investigational medicinal product code
    Other name
    Dasiglucagon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.2 mg ZP4207 in solution was administered via disposable dosing syringe. The subcutaneous injection was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Arm title
    		 0.6 mg ZP4207 - hypoglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.6 mg ZP4207 at hypoglycemic state, however at different trial visits
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZP4207 - 0.6 mg
    Investigational medicinal product code
    Other name
    Dasiglucagon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.6 mg ZP4207 in solution was administered via disposable dosing syringe. The subcutaneous injection was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Arm title
    		 0.03 mg Lilly Glucagon - euglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.03 mg Lilly Glucagon at euglycemic state, however at different trial visits
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lilly Glucagon - 0.03 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.03 mg Glucagon was administered via disposable dosing syringe. The subcutaneous injection was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Arm title
    		 0.08 mg Lilly Glucagon - euglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.08 mg Lilly Glucagon at euglycemic state, however at different trial visits
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lilly Glucagon - 0.08 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.08 mg Glucagon was administered via disposable dosing syringe. The subcutaneous injection was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Arm title
    		 0.2 mg Lilly Glucagon - Euglycemic condition
    Arm description
    		 Due to the design of the trial all patients received one dose of 0.2 mg Lilly Glucagon at euglycemic state, however at different trial visits
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lilly Glucagon - 0.2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A single dose of 0.2 mg Glucagon was administered via disposable dosing syringe. The subcutaneous injection was given into the abdominal skin in the peri-umbilical area by trained personnel.

    Number of subjects in period 1
    		0.03 mg ZP4207 - euglycemic condition 0.08 mg ZP4207 - euglycemic condition 0.2 mg ZP4207 - euglycemic condition 0.6 mg ZP4207 - euglycemic condition 0.03 mg ZP4207 - hypoglycemic condition 0.08 mg ZP4207 - hypoglycemic condition 0.2 mg ZP4207 - hypoglycemic condition 0.6 mg ZP4207 - hypoglycemic condition 0.03 mg Lilly Glucagon - euglycemic condition 0.08 mg Lilly Glucagon - euglycemic condition 0.2 mg Lilly Glucagon - Euglycemic condition
    Started
    16
    17
    16
    17
    17
    17
    17
    17
    17
    17
    16
    Completed
    16
    17
    16
    17
    17
    17
    17
    17
    17
    17
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 Safety analysis set - all patients exposed

    Reporting group values
    		 Overall Total
    Number of subjects
    		 23 23
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 23 23
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.2 ( 13.07 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 14 14
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    		 176.26 ( 7.442 ) -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 78.24 ( 9.311 ) -
    BMI
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 25.21 ( 2.927 ) -
    HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    		 7.42 ( 0.578 ) -
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set consist of patients enrolled according to protocol amendment 3.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set includes all patients receiving at least one dose of the IMP (including the first 6 patients).

    Subject analysis sets values
    		 Full analysis set Safety analysis set
    Number of subjects
    17
    23
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    17
    23
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.9 ( 14.21 )
    44.2 ( 13.07 )
    Gender categorical
    Units: Subjects
        Female
    7
    9
        Male
    10
    14
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    176.24 ( 6.6945 )
    176.26 ( 7.442 )
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    79.52 ( 8.613 )
    78.24 ( 9.311 )
    BMI
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    25.65 ( 3.061 )
    25.21 ( 2.927 )
    HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    7.48 ( 0.472 )
    7.42 ( 0.578 )

    End points

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    End points reporting groups
    Reporting group title
    0.03 mg ZP4207 - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.03 mg ZP4207 at euglycemic state however at different trial visits.

    Reporting group title
    0.08 mg ZP4207 - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.08 mg ZP4207 at euglycemic state however at different trial visits.

    Reporting group title
    0.2 mg ZP4207 - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.2 mg ZP4207 at euglycemic state however at different trial visits

    Reporting group title
    0.6 mg ZP4207 - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.6 mg ZP4207 at euglycemic state, however at different trial visits

    Reporting group title
    0.03 mg ZP4207 - hypoglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.03 mg ZP4207 at hypoglycemic state, however at different trial visits

    Reporting group title
    0.08 mg ZP4207 - hypoglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.08 mg ZP4207 at hypoglycemic state, however at different trial visits

    Reporting group title
    0.2 mg ZP4207 - hypoglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.2 mg ZP4207 at hyopglycemic state, however at different trial visits

    Reporting group title
    0.6 mg ZP4207 - hypoglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.6 mg ZP4207 at hypoglycemic state, however at different trial visits

    Reporting group title
    0.03 mg Lilly Glucagon - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.03 mg Lilly Glucagon at euglycemic state, however at different trial visits

    Reporting group title
    0.08 mg Lilly Glucagon - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.08 mg Lilly Glucagon at euglycemic state, however at different trial visits

    Reporting group title
    0.2 mg Lilly Glucagon - Euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients received one dose of 0.2 mg Lilly Glucagon at euglycemic state, however at different trial visits

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set consist of patients enrolled according to protocol amendment 3.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set includes all patients receiving at least one dose of the IMP (including the first 6 patients).

    Primary: Pharmacokinetics - Area under the plasma concentration curve (0-240 minutes)

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    End point title
    		 Pharmacokinetics - Area under the plasma concentration curve (0-240 minutes)
    End point description
    AUC(0-240min), area under the plasma ZP4207 and baseline adjusted plasma glucagon concentration curve from 0 to 240 minutes post-dose
    End point type
    Primary
    End point timeframe
    From dosing and untill 240 minutes post-dose
    End point values
    		 0.03 mg ZP4207 - euglycemic condition 0.08 mg ZP4207 - euglycemic condition 0.2 mg ZP4207 - euglycemic condition 0.6 mg ZP4207 - euglycemic condition 0.03 mg ZP4207 - hypoglycemic condition 0.08 mg ZP4207 - hypoglycemic condition 0.2 mg ZP4207 - hypoglycemic condition 0.6 mg ZP4207 - hypoglycemic condition 0.03 mg Lilly Glucagon - euglycemic condition 0.08 mg Lilly Glucagon - euglycemic condition 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects analysed
    16
    17
    16
    17
    17
    17
    17
    17
    17
    17
    16
    Units: pmol*h/L
        geometric mean (geometric coefficient of variation)
    169 ( 25.1 )
    549 ( 23.3 )
    1260 ( 19.6 )
    3570 ( 16.5 )
    168 ( 24.7 )
    589 ( 21.5 )
    1280 ( 16.3 )
    3490 ( 20.3 )
    49.8 ( 39.0 )
    129 ( 26.4 )
    349 ( 30.7 )
    Statistical analysis title
    		 AUC(0-240min) - ZP4207/Lilly Glucagon - 0.03 mg
    Statistical analysis description
    Comparison of AUC (0-240 min) for 0.03 mg ZP4207 vs 0.03 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.03 mg Lilly Glucagon - euglycemic condition v 0.03 mg ZP4207 - euglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    3.37
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.95
         upper limit
    		 3.84
    Notes
    [1] - No defined H0-hypothesis
    Statistical analysis title
    		 AUC(0-240min) - ZP4207/Lilly Glucagon - 0.08 mg
    Statistical analysis description
    Comparison of AUC (0-240 min) for 0.08 mg ZP4207 vs 0.08 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    4.27
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 3.75
         upper limit
    		 4.86
    Notes
    [2] - No defined H0-hypothesis
    Statistical analysis title
    		 AUC(0-240min) - ZP4207/Lilly Glucagon - 0.2 mg
    Statistical analysis description
    Comparison of AUC (0-240 min) for 0.2 mg ZP4207 vs 0.2 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    3.62
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 3.17
         upper limit
    		 4.14
    Notes
    [3] - No defined H0-hypothesis
    Statistical analysis title
    		 AUC(0-240min) - ZP4207 Eugly/hypogly state 0.03 mg
    Statistical analysis description
    Comparison of AUC (0-240 min) for 0.03 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.993
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.916
         upper limit
    		 1.077
    Notes
    [4] - No defined H0-hypothesis
    Statistical analysis title
    		 AUC(0-240min) - ZP4207 Eugly/hypogly state 0.08 mg
    Statistical analysis description
    Comparison of AUC (0-240 min) for 0.08 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.931
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.009
    Notes
    [5] - No defined H0-hypothesis
    Statistical analysis title
    		 AUC(0-240min) - ZP4207 Eugly/hypogly state 0.2 mg
    Statistical analysis description
    Comparison of AUC (0-240 min) for 0.2 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.986
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.909
         upper limit
    		 1.07
    Notes
    [6] - No defined H0-hypothesis
    Statistical analysis title
    		 AUC(0-240min) - ZP4207 Eugly/hypogly state 0.6 mg
    Statistical analysis description
    Comparison of AUC (0-240 min) for 0.6 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.6 mg ZP4207 - euglycemic condition v 0.6 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.968
         upper limit
    		 1.076
    Notes
    [7] - No defined H0-hypothesis

    Primary: Pharmacokinetics - Cmax

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    End point title
    		 Pharmacokinetics - Cmax
    End point description
    Cmax,maximum of all valid plasma ZP4207 and baseline adjusted plasma glucagon concentration measurements from 0 to 240 minutes post-dose
    End point type
    Primary
    End point timeframe
    From dosing and untill 240 minutes post-dose
    End point values
    		 0.03 mg ZP4207 - euglycemic condition 0.08 mg ZP4207 - euglycemic condition 0.2 mg ZP4207 - euglycemic condition 0.6 mg ZP4207 - euglycemic condition 0.03 mg ZP4207 - hypoglycemic condition 0.08 mg ZP4207 - hypoglycemic condition 0.2 mg ZP4207 - hypoglycemic condition 0.6 mg ZP4207 - hypoglycemic condition 0.03 mg Lilly Glucagon - euglycemic condition 0.08 mg Lilly Glucagon - euglycemic condition 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects analysed
    16
    17
    16
    17
    17
    17
    17
    17
    17
    17
    16
    Units: picomol/L
        geometric mean (geometric coefficient of variation)
    142 ( 33.6 )
    387 ( 31.8 )
    733 ( 33.2 )
    1970 ( 25.9 )
    129 ( 33.5 )
    422 ( 38.8 )
    810 ( 22.7 )
    1940 ( 26.0 )
    74.7 ( 42.8 )
    160 ( 29.2 )
    420 ( 30.2 )
    Statistical analysis title
    		 Cmax - ZP4207/Lilly Glucagon 0.03 mg
    Statistical analysis description
    Comparison of Cmax for 0.03 mg ZP4207 vs 0.03 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Cmax Ratio
    Point estimate
    1.89
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.64
         upper limit
    		 2.18
    Notes
    [8] - Descriptive analysis
    Statistical analysis title
    		 Cmax - ZP4207/Lilly Glucagon 0.08 mg
    Statistical analysis description
    Comparison of Cmax for 0.08 mg ZP4207 vs 0.08 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Cmax Ratio
    Point estimate
    2.42
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 2.78
    Notes
    [9] - Descriptive analysis
    Statistical analysis title
    		 Cmax - ZP4207/Lilly Glucagon 0.2 mg
    Statistical analysis description
    Comparison of Cmax for 0.08 mg ZP4207 vs 0.08 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 Cmax Ratio
    Point estimate
    1.74
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.51
         upper limit
    		 2.02
    Notes
    [10] - Descriptive analysis
    Statistical analysis title
    		 Cmax - ZP4207 Eugly/hypogly state 0.03 mg
    Statistical analysis description
    Comparison of Cmax for 0.03 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Cmax Ratio
    Point estimate
    1.08
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.23
    Notes
    [11] - Descriptive analysis
    Statistical analysis title
    		 Cmax - ZP4207 Eugly/hypogly state 0.08 mg
    Statistical analysis description
    Comparison of Cmax for 0.08 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Cmax Ratio
    Point estimate
    0.918
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.807
         upper limit
    		 1.043
    Notes
    [12] - Descriptive analysis
    Statistical analysis title
    		 Cmax - ZP4207 Eugly/hypogly state 0.2 mg
    Statistical analysis description
    Comparison of Cmax for 0.2mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    Method
    Parameter type
    		 Cmax Ratio
    Point estimate
    0.914
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.802
         upper limit
    		 1.041
    Notes
    [13] - Descriptive analysis
    Statistical analysis title
    		 Cmax - ZP4207 Eugly/hypogly state 0.6 mg
    Statistical analysis description
    Comparison of Cmax for 0.6 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.6 mg ZP4207 - euglycemic condition v 0.6 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    Method
    Parameter type
    		 Cmax Ratio
    Point estimate
    1.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.915
         upper limit
    		 1.117
    Notes
    [14] - Descriptive analysis

    Primary: Pharmacokinetics - Tmax

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    End point title
    		 Pharmacokinetics - Tmax
    End point description
    tmax, time to maximum of plasma ZP4207 and baseline adjusted plasma glucagon concentration measurements
    End point type
    Primary
    End point timeframe
    From dosing and untill 240 minutes post-dose
    End point values
    		 0.03 mg ZP4207 - euglycemic condition 0.08 mg ZP4207 - euglycemic condition 0.2 mg ZP4207 - euglycemic condition 0.6 mg ZP4207 - euglycemic condition 0.03 mg ZP4207 - hypoglycemic condition 0.08 mg ZP4207 - hypoglycemic condition 0.2 mg ZP4207 - hypoglycemic condition 0.6 mg ZP4207 - hypoglycemic condition 0.03 mg Lilly Glucagon - euglycemic condition 0.08 mg Lilly Glucagon - euglycemic condition 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects analysed
    16
    17
    16
    17
    17
    17
    17
    17
    17
    17
    16
    Units: hour
        median (full range (min-max))
    0.500 (0.25 to 1.00)
    0.500 (0.25 to 1.50)
    0.500 (0.50 to 1.50)
    0.500 (0.25 to 1.00)
    0.500 (0.25 to 1.00)
    0.500 (0.25 to 1.00)
    0.500 (0.25 to 1.00)
    0.500 (0.25 to 1.00)
    0.250 (0.08 to 0.50)
    0.250 (0.25 to 0.50)
    0.250 (0.25 to 0.50)
    Statistical analysis title
    		 Estimate of diff. - ZP4207/Lilly Glucagon 0.03 mg
    Statistical analysis description
    Point estimate of median of differences (ZP4207 - Lilly GlucagonTM) according to Hodges and Lehmann
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    Method
    Parameter type
    		 Point estimate of difference
    Point estimate
    0.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.25
    Notes
    [15] - Descriptive analysis
    Statistical analysis title
    		 Estimate of diff. - ZP4207/Lilly Glucagon 0.08 mg
    Statistical analysis description
    Point estimate of median of differences (ZP4207 - Lilly GlucagonTM) according to Hodges and Lehmann
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    Method
    Parameter type
    		 Point estimate of difference
    Point estimate
    0.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.25
    Notes
    [16] - Descriptive analysis
    Statistical analysis title
    		 Estimate of diff. - ZP4207/Lilly Glucagon 0.2mg
    Statistical analysis description
    Point estimate of median of differences (ZP4207 - Lilly GlucagonTM) according to Hodges and Lehmann
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    Method
    Parameter type
    		 Point estimate of difference
    Point estimate
    0.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.5
    Notes
    [17] - Descriptive analysis
    Statistical analysis title
    		 Estimate of diff ZP4207 eugly/hypogly state 0.03mg
    Statistical analysis description
    Point estimate of median of differences (ZP4207 - Euglycemic vs Hypoglycemic state) according to Hodges and Lehmann
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    Method
    Parameter type
    		 Point estimate of difference
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0
    Notes
    [18] - Descriptive analysis
    Statistical analysis title
    		 Estimate of diff ZP4207 eugly/hypogly state 0.08mg
    Statistical analysis description
    Point estimate of median of differences (ZP4207 - Euglycemic vs Hypoglycemic state) according to Hodges and Lehmann
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    Method
    Parameter type
    		 Point estimate of difference
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [19] - Descriptive analysis
    Statistical analysis title
    		 Estimate of diff ZP4207 eugly/hypogly state 0.2mg
    Statistical analysis description
    Point estimate of median of differences (ZP4207 - Euglycemic vs Hypoglycemic state) according to Hodges and Lehmann
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    Method
    Parameter type
    		 Point estimate of difference
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [20] - Descriptive analysis
    Statistical analysis title
    		 Estimate of diff ZP4207 eugly/hypogly state 0.6mg
    Statistical analysis description
    Point estimate of median of differences (ZP4207 - Euglycemic vs Hypoglycemic state) according to Hodges and Lehmann
    Comparison groups
    0.6 mg ZP4207 - euglycemic condition v 0.6 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    Method
    Parameter type
    		 Point estimate of difference
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [21] - Descriptive analysis

    Primary: Pharmacodynamics - Area under the effect curve (0-240 minutes)

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    End point title
    		 Pharmacodynamics - Area under the effect curve (0-240 minutes)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 hours after dose
    End point values
    		 0.03 mg ZP4207 - euglycemic condition 0.08 mg ZP4207 - euglycemic condition 0.2 mg ZP4207 - euglycemic condition 0.6 mg ZP4207 - euglycemic condition 0.03 mg ZP4207 - hypoglycemic condition 0.08 mg ZP4207 - hypoglycemic condition 0.2 mg ZP4207 - hypoglycemic condition 0.6 mg ZP4207 - hypoglycemic condition 0.03 mg Lilly Glucagon - euglycemic condition 0.08 mg Lilly Glucagon - euglycemic condition 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects analysed
    16
    17
    16
    17
    17
    17
    17
    17
    17
    17
    16
    Units: mg.h/L
        arithmetic mean (standard deviation)
    105 ( 87.9 )
    242 ( 149 )
    386 ( 146 )
    479 ( 159 )
    70.6 ( 100 )
    249 ( 201 )
    406 ( 175 )
    535 ( 187 )
    49.7 ( 53.3 )
    112 ( 102 )
    179 ( 115 )
    Statistical analysis title
    		 AUE(0-240min) - ZP4207/Lilly Glucagon - 0.03 mg
    Statistical analysis description
    Comparison of AUE (0-240 min) for 0.03 mg ZP4207 vs 0.03 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    2.26
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.3058
         upper limit
    		 3.9042
    Notes
    [22] - No defined H0-hypothesis
    Statistical analysis title
    		 AUE(0-240min) - ZP4207/Lilly Glucagon - 0.08 mg
    Statistical analysis description
    Comparison of AUE (0-240 min) for 0.08 mg ZP4207 vs 0.08 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    4.09
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.4691
         upper limit
    		 6.7835
    Notes
    [23] - No defined H0-hypothesis
    Statistical analysis title
    		 AUE(0-240min) - ZP4207/Lilly Glucagon - 0.2 mg
    Statistical analysis description
    Comparison of AUE (0-240 min) for 0.2 mg ZP4207 vs 0.2 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    2.46
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.4434
         upper limit
    		 4.1772
    Notes
    [24] - No defined H0-hypothesis
    Statistical analysis title
    		 AUE(0-240min) - ZP4207 Eugly/hypogly state 0.03 mg
    Statistical analysis description
    Comparison of AUE (0-240 min) for 0.03 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    2.21
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2481
         upper limit
    		 3.3907
    Notes
    [25] - No defined H0-hypothesis
    Statistical analysis title
    		 AUE(0-240min) - ZP4207 Eugly/hypogly state 0.08 mg
    Statistical analysis description
    Comparison of AUE (0-240 min) for 0.08 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.21
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7153
         upper limit
    		 2.036
    Notes
    [26] - No defined H0-hypothesis
    Statistical analysis title
    		 AUE(0-240min) - ZP4207 Eugly/hypogly state 0.2 mg
    Statistical analysis description
    Comparison of AUE (0-240 min) for 0.2 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.865
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.5075
         upper limit
    		 1.4748
    Notes
    [27] - No defined H0-hypothesis
    Statistical analysis title
    		 AUE(0-240min) - ZP4207 Eugly/hypogly state 0.6 mg
    Statistical analysis description
    Comparison of AUE (0-240 min) for 0.6 mg ZP4207 at euglycemic vs hypoglycemic condition
    Comparison groups
    0.6 mg ZP4207 - euglycemic condition v 0.6 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.908
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7408
         upper limit
    		 1.1128
    Notes
    [28] - No defined H0-hypothesis

    Primary: Pharmacodynamics - CEmax

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    End point title
    		 Pharmacodynamics - CEmax
    End point description
    PD endpoints were derived from the plasma glucose profiles above baseline, where baseline was defined as the pre-dose measurement prior to each dosing. The endpoints were calculated in accordance with model 220 of Phoenix/WinNonLin.
    End point type
    Primary
    End point timeframe
    Baseline to 4 hours after dose
    End point values
    		 0.03 mg ZP4207 - euglycemic condition 0.08 mg ZP4207 - euglycemic condition 0.2 mg ZP4207 - euglycemic condition 0.6 mg ZP4207 - euglycemic condition 0.03 mg ZP4207 - hypoglycemic condition 0.08 mg ZP4207 - hypoglycemic condition 0.2 mg ZP4207 - hypoglycemic condition 0.6 mg ZP4207 - hypoglycemic condition 0.03 mg Lilly Glucagon - euglycemic condition 0.08 mg Lilly Glucagon - euglycemic condition 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects analysed
    16
    17
    16
    17
    17
    17
    17
    17
    17
    17
    15
    Units: mg/dL
        arithmetic mean (standard deviation)
    54.0 ( 32.9 )
    101 ( 44.4 )
    139 ( 42.7 )
    165 ( 46.1 )
    37.9 ( 38.9 )
    106 ( 61.1 )
    154 ( 48.4 )
    192 ( 54.1 )
    32.6 ( 25.2 )
    59.5 ( 36.3 )
    86.1 ( 38.2 )
    Statistical analysis title
    		 CEmax - ZP4207/Lilly Glucagon - 0.03 mg
    Statistical analysis description
    Comparison of CEmax for 0.03 mg ZP4207 vs 0.03 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.47
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.1865
         upper limit
    		 1.8132
    Notes
    [29] - No defined H0-hypothesis
    Statistical analysis title
    		 CEmax - ZP4207 Eugly/hypogly state 0.08 mg
    Statistical analysis description
    Comparison of CEmax for 0.08 mg ZP4207 vs 0.08 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.85
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.5175
         upper limit
    		 2.253
    Notes
    [30] - No defined H0-hypothesis
    Statistical analysis title
    		 CEmax - ZP4207/Lilly Glucagon - 0.2 mg
    Statistical analysis description
    Comparison of CEmax for 0.2 mg ZP4207 vs 0.2 mg Lilly Glucagon at euglycemic condition
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.69
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.3767
         upper limit
    		 2.0687
    Notes
    [31] - No defined H0-hypothesis
    Statistical analysis title
    		 CEmax - ZP4207 Eugly/hypogly state 0.03 mg
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, glycemic state, dose, their interaction, period, sequence and patient within sequence as fixed effects. Point estimate is the ratio of geometric LS-means of glycemic states (euglycemic/hypoglycemic) for the 0.03mg dose.
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.65
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.1848
         upper limit
    		 2.2855
    Notes
    [32] - No defined H0-hypothesis
    Statistical analysis title
    		 CEmax - ZP4207 Eugly/hypogly state 0.08 mg
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, glycemic state, dose, their interaction, period, sequence and patient within sequence as fixed effects. Point estimate is the ratio of geometric LS-means of glycemic states (euglycemic/hypoglycemic) for the 0.08mg dose.
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    1.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7559
         upper limit
    		 1.3761
    Notes
    [33] - No defined H0-hypothesis
    Statistical analysis title
    		 CEmax - ZP4207 Eugly/hypogly state 0.2 mg
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, glycemic state, dose, their interaction, period, sequence and patient within sequence as fixed effects. Point estimate is the ratio of geometric LS-means of glycemic states (euglycemic/hypoglycemic) for the 0.2mg dose.
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.838
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.6174
         upper limit
    		 1.1375
    Notes
    [34] - No defined H0-hypothesis
    Statistical analysis title
    		 CEmax - ZP4207 Eugly/hypogly state 0.6 mg
    Statistical analysis description
    Analysis of variance (ANOVA) with log-transformed response, glycemic state and patient as fixed effect. Point estimate is the ratio of geometric LS-means of glycemic states (euglycemic/hypoglycemic) for the 0.6mg dose.
    Comparison groups
    0.6 mg ZP4207 - euglycemic condition v 0.6 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    Method
    Parameter type
    		 least squares mean ratio
    Point estimate
    0.859
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7597
         upper limit
    		 0.9722
    Notes
    [35] - No defined H0-hypothesis

    Primary: Pharmacodynamics - TEmax

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    End point title
    		 Pharmacodynamics - TEmax
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 hours after dose
    End point values
    		 0.03 mg ZP4207 - euglycemic condition 0.08 mg ZP4207 - euglycemic condition 0.2 mg ZP4207 - euglycemic condition 0.6 mg ZP4207 - euglycemic condition 0.03 mg ZP4207 - hypoglycemic condition 0.08 mg ZP4207 - hypoglycemic condition 0.2 mg ZP4207 - hypoglycemic condition 0.6 mg ZP4207 - hypoglycemic condition 0.03 mg Lilly Glucagon - euglycemic condition 0.08 mg Lilly Glucagon - euglycemic condition 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects analysed
    16
    17
    16
    17
    17
    17
    17
    17
    17
    17
    15
    Units: minute
        arithmetic mean (standard deviation)
    56.9 ( 24.4 )
    84.1 ( 27.2 )
    98.8 ( 31.8 )
    119 ( 43.6 )
    45.9 ( 27.4 )
    69.0 ( 16.6 )
    87.6 ( 25.4 )
    102 ( 28.3 )
    32.9 ( 19.6 )
    43.5 ( 19.7 )
    52.7 ( 18.3 )
    Statistical analysis title
    		 TEmax - ZP4207/Lilly Glucagon - 0.03 mg
    Statistical analysis description
    Point estimate of median of differences (ZP4207 - Lilly GlucagonTM) for 0.03mg dose according to Hodges and Lehmann
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [36]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    20
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 20
         upper limit
    		 40
    Notes
    [36] - No defined H0-hypothesis
    Statistical analysis title
    		 TEmax - ZP4207/Lilly Glucagon - 0.08 mg
    Statistical analysis description
    Point estimate of median of differences (ZP4207 - Lilly GlucagonTM) for 0.08mg dose according to Hodges and Lehmann
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg Lilly Glucagon - euglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    40
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 20
         upper limit
    		 40
    Notes
    [37] - No defined H0-hypothesis
    Statistical analysis title
    		 TEmax - ZP4207/Lilly Glucagon - 0.2 mg
    Statistical analysis description
    Point estimate of median of differences (ZP4207 - Lilly GlucagonTM) for 0.2mg dose according to Hodges and Lehmann
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg Lilly Glucagon - Euglycemic condition
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other [38]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    40
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 20
         upper limit
    		 60
    Notes
    [38] - No defined H0-hypothesis
    Statistical analysis title
    		 TEmax - ZP4207 Eugly/hypogly state 0.03 mg
    Statistical analysis description
    Point estimate of median of differences (euglycemic - hypoglycemic) for the 0.03mg dose according to Hodges and Lehmann
    Comparison groups
    0.03 mg ZP4207 - euglycemic condition v 0.03 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 20
    Notes
    [39] - No defined H0-hypothesis
    Statistical analysis title
    		 TEmax - ZP4207 Eugly/hypogly state 0.08 mg
    Statistical analysis description
    Point estimate of median of differences (euglycemic - hypoglycemic) for the 0.08mg dose according to Hodges and Lehmann
    Comparison groups
    0.08 mg ZP4207 - euglycemic condition v 0.08 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [40]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    17
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 20
    Notes
    [40] - No defined H0-hypothesis
    Statistical analysis title
    		 TEmax - ZP4207 Eugly/hypogly state 0.2 mg
    Statistical analysis description
    Point estimate of median of differences (euglycemic - hypoglycemic) for the 0.2mg dose according to Hodges and Lehmann
    Comparison groups
    0.2 mg ZP4207 - euglycemic condition v 0.2 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [41]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 20
    Notes
    [41] - No defined H0-hypothesis
    Statistical analysis title
    		 TEmax - ZP4207 Eugly/hypogly state 0.6 mg
    Statistical analysis description
    Point estimate of median of differences (euglycemic - hypoglycemic) for the 0.6mg dose according to Hodges and Lehmann
    Comparison groups
    0.6 mg ZP4207 - euglycemic condition v 0.6 mg ZP4207 - hypoglycemic condition
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [42]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 20
    Notes
    [42] - No defined H0-hypothesis

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the first trial-related activity after the patient had signed the informed consent to the end of the follow-up period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    0.03 mg ZP4207 - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.03 mg ZP4207 at euglycemic state however at different trial visits.

    Reporting group title
    0.08 mg ZP4207 - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.08 mg ZP4207 at euglycemic state however at different trial visits.

    Reporting group title
    0.2 mg ZP4207 - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.2 mg ZP4207 at euglycemic state however at different trial visits

    Reporting group title
    0.6 mg ZP4207 - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.03 mg ZP4207 at euglycemic state, however at different trial visits

    Reporting group title
    0.03 mg ZP4207 - hypoglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.03 mg ZP4207 at hypoglycemic state, however at different trial visits

    Reporting group title
    0.08 mg ZP4207 - hypoglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.08 mg ZP4207 at hypoglycemic state, however at different trial visits

    Reporting group title
    0.2 mg ZP4207 - hypoglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.2 mg ZP4207 at hyopglycemic state, however at different trial visits

    Reporting group title
    0.6 mg ZP4207 - hypoglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.6 mg ZP4207 at hypoglycemic state, however at different trial visits

    Reporting group title
    0.03 mg Lilly Glucagon - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.03 mg Lilly Glucagon at euglycemic state, however at different trial visits

    Reporting group title
    0.08 mg Lilly Glucagon - euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.08 mg Lilly Glucagon at euglycemic state, however at different trial visits

    Reporting group title
    0.2 mg Lilly Glucagon - Euglycemic condition
    Reporting group description
    		 Due to the design of the trial all patients recieved one dose of 0.2 mg Lilly Glucagon at euglycemic state, however at different trial visits

    Serious adverse events
    		 0.03 mg ZP4207 - euglycemic condition 0.08 mg ZP4207 - euglycemic condition 0.2 mg ZP4207 - euglycemic condition 0.6 mg ZP4207 - euglycemic condition 0.03 mg ZP4207 - hypoglycemic condition 0.08 mg ZP4207 - hypoglycemic condition 0.2 mg ZP4207 - hypoglycemic condition 0.6 mg ZP4207 - hypoglycemic condition 0.03 mg Lilly Glucagon - euglycemic condition 0.08 mg Lilly Glucagon - euglycemic condition 0.2 mg Lilly Glucagon - Euglycemic condition
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 0.03 mg ZP4207 - euglycemic condition 0.08 mg ZP4207 - euglycemic condition 0.2 mg ZP4207 - euglycemic condition 0.6 mg ZP4207 - euglycemic condition 0.03 mg ZP4207 - hypoglycemic condition 0.08 mg ZP4207 - hypoglycemic condition 0.2 mg ZP4207 - hypoglycemic condition 0.6 mg ZP4207 - hypoglycemic condition 0.03 mg Lilly Glucagon - euglycemic condition 0.08 mg Lilly Glucagon - euglycemic condition 0.2 mg Lilly Glucagon - Euglycemic condition
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
    7 / 20 (35.00%)
    12 / 20 (60.00%)
    10 / 17 (58.82%)
    4 / 20 (20.00%)
    6 / 20 (30.00%)
    5 / 20 (25.00%)
    9 / 17 (52.94%)
    3 / 21 (14.29%)
    3 / 20 (15.00%)
    6 / 20 (30.00%)
    Injury, poisoning and procedural complications
    Application site haematoma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    2 / 20 (10.00%)
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    2 / 20 (10.00%)
    2 / 20 (10.00%)
    1 / 17 (5.88%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    1
    2
    1
    1
    2
    2
    1
    1
    1
    3
    Orthostatic intolerance
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    2
    Injection site oedema
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Injection site pruritus
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
    5 / 20 (25.00%)
    11 / 20 (55.00%)
    8 / 17 (47.06%)
    2 / 20 (10.00%)
    2 / 20 (10.00%)
    5 / 20 (25.00%)
    7 / 17 (41.18%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    4 / 20 (20.00%)
         occurrences all number
    1
    5
    11
    8
    2
    2
    5
    7
    0
    1
    4
    Toothache
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 20 (10.00%)
    5 / 20 (25.00%)
    3 / 17 (17.65%)
    1 / 20 (5.00%)
    2 / 20 (10.00%)
    2 / 20 (10.00%)
    4 / 17 (23.53%)
    0 / 21 (0.00%)
    2 / 20 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    2
    5
    3
    1
    3
    2
    4
    0
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2016
    This amendment was created after blinded review of PD data of the first 6 patients. Glucagon action was found to be difficult to assess due to a too high insulin infusion rate before and during the clamp procedure. To address this issue the following changes were introduced: • the i.v. insulin infusion rate was reduced and made more flexible to better match individual patients’ needs. • the threshold for initiation of the i.v. glucose infusion during the euglycemic clamp assessment was increased to avoid time in hypoglycemia. • the first 6 patients were withdrawn from the trial (impact on statistical analysis could not be ruled out due to possible glucose counter-regulatory responses to hypoglycemia). Five (5) of these patients were withdrawn as per Investigator’s decision, and one patient who belonged also to the group of patients meeting the criteria for exclusion described in the protocol amendment actually decided on own initiative to discontinue the trial. The withdrawn patients did not continue the trial but attended a complete follow-up examination in accordance with the protocol. • since the 6 patients needed to be replaced to have at least 15 completers, replacement and re-screening criteria in the protocol were modified. o new patients received the same randomization/treatment sequence as the initial 6 patients. o replacements were performed to ensure that at least 15 patients complete Visit 5 with sufficient evaluable data to perform statistical analysis. o re-screening of eligible patients (who were not yet randomized) was possible. In that case, a new informed consent had to be signed and dated. • the primary endpoint (AUE0-240min) was explained to be calculated up to the last measurement prior to intervention in case of premature glucose infusion intervention. • PK/PD data for these first 6 patients were reported separately. Data from the first 6 patients were excluded from FAS.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30350477
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